In the human liver, ethanol is degraded by dimeric alcohol dehydrogenase (ADH) to acetaldehyde (AcH) and then by tetrameric aldehyde dehydrogenase (ALDH) with the subsequent production of acetate, and finally Co 2 and H20. The genetic polymorphisms at the ADH and ALDH loci are suspected to have importance in determining the degree of susceptibility to ethanol. Thus, to understand the genetics of alcohol sensitivity and alcoholism, it is important to evaluate the molecular structure of the ADH and ALDH genes. As an initial step toward that end, we plan to characterize different ADH genes at the molecular level. So far, molecular characterization of the ADH genes has been mostly at the cDNA level and only the genomic structure of the ADH2 locus has been elucidated. As an initial step toward the understanding of the genetics of alcohol sensitivity, we propose to characterize all ADH genes, including not only those at the ADH1, ADH2, and ADH3 loci of class I but also those of the class II and III loci. Using DNA from the PI, we have isolated partial genomic clones not only of all these ADH genes but also of a new ADH gene which was previously unknown. In order to characterize all of these ADH genes completely, we propose to construct a library using the same genomic DNA, screen it, and perform DNA sequencing. By using the DNA sequence data obtained, we plan to study DNA polymorphism at informative regions at each ADH locus by the method of polymerase chain reaction and direct genomic sequencing. These data and other published data will also be used to study the pattern of ADH gene differentiation.